Project Summary/Abstract This proposal for a Mentored Research Scientist Development Award is designed to provide the candidate the necessary time and resources to transit into an independent statistical geneticist and genetic epidemiologist in cardiovascular diseases, particularly in congenital heart defects (CHDs). This goal will be achieved through enhanced training and research experience: 1) by taking didactic courses in areas related to birth defects epidemiology, reproductive genetics and integrative genomics methodologies; 2) by implementing research projects for genomic and epigenomic studies of CHDs; and 3) by assembling an expert panel of mentors with extensive and complementary skills. The proposed K01 program will complement the candidate's previous training in statistics, epidemiology and quantitative biology, optimize his effort to complete the proposed research projects, and allow him to become an independent investigator. The (co-)mentors, Drs. Nianjun Liu and John S. Witte, will advise the candidate's training in the domain of integrative genomics methodologies. The (co-)mentors, Drs. Charlotte A. Hobbs, Benjamin Tycko and Jiali Han will advise the candidate's training in the domain of birth genetics epidemiology and reproductive genetics. In the proposed projects, innovative biostatistical approaches will be developed and applied to samples from the National Birth Defect Prevention Study (NBDPS), the largest multi-site population-based study of birth defects ever conducted. We will utilize the genomic data (i.e. ~ 5 million genetic variants) of ~ 1,000 case mother-father-infant triads and ~ 1,000 control mother-infant dyads, and the epigenetic data (i.e. ~ 450K methylation sites) of 71 cardiac tissue samples. The proposed projects will address three challenges in CHD research: 1) the genetic heterogeneity of CHDs, known as ?all happy families are alike, each unhappy family is unhappy in its own way?; 2) the functional effects of genetic variants within specific tissues, such as the association between genetic variations and epigenetic modifications; and 3) the complex interactions underlying CHDs, including the high-order interactions among genetic variants, epigenetic modifications and maternal life style factors. The candidate has successfully completed a two-year KL2 Mentored Career Development Award, entitled ?detecting gene-by-gene and gene-by-environment interactions associated with CHDs?, which provides a foundation onto which we will build more detailed studies to address the proposed topics. The findings will likely provide insights into the underlying pathophysiological and etiological processes that result in CHDs, and more importantly, can provide a direction for translational research leading to more precise preconceptional counseling and interventions. The training and research experience gained from the proposed study will serve as the groundwork for an independent research program, including a new R01 proposal to expand upon the research that will be initiated through this proposed K01 program.